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Ref Type Abstract
PMID
Authors Luna De Sutter; Agnieszka Wozniak; Jasper Verreet; Ulla Vanleeuw; Lore De Cock; Nina Linde; Christine Drechsler; Christina Esdar; Raf Sciot; Patrick Schoffski
Title Anti-tumor effects of the novel KIT mutant inhibitor M4205 in patient-derived gastrointestinal stromal tumor (GIST) xenograft models
Journal Vol Issue Date Pages Journal Short Title
Cancer Research 82 12_Supplement June 15, 2022
URL https://aacrjournals.org/cancerres/article/82/12_Supplement/2666/699884/Abstract-2666-Anti-tumor-effects-of-the-novel-KIT
Abstract Text Background: The majority of GISTs are driven by constitutively activated KIT/PDGFRA kinases and susceptible to treatment with tyrosine kinase inhibitors such as imatinib, sunitinib and regorafenib. During treatment most tumors will develop heterogeneous secondary mutations in KIT or PDGFRA inducing drug resistance, so there is an unmet need for novel therapies. We tested the efficacy of M4205, a novel specific KIT inhibitor with high activity towards the most relevant KIT mutations, in patient-derived GIST xenograft models. Methods: NMRI nu/nu mice (n=146) were transplanted with patient-derived GIST xenograft models UZLX-GIST9 (KIT:p.P577del;W557LfsX5;D820G) known to be resistant to both imatinib and sunitinib, with the dose-dependent imatinib-sensitive and sunitinib-sensitive models UZLX-GIST2B (KIT:p.A502_Y503dup), UZLX-GIST25 (KIT: p.K642E) and the cell-line derived model GIST882 (KIT: p.K642E)*. Mice were treated daily with vehicle (control), imatinib (100mg/kg), avapritinib (5mg/kg), sunitinib (20mg/kg), or M4205 (10mg/kg, 25mg/kg). Efficacy was assessed by tumor volume evolution, histopathology [hematoxilin & eosine staining (H&E)] and immunohistochemistry [Ki-67, phospho-Histone H3 (pHH3), cleaved PARP]. Histologic response (HR) was graded as previously described°. Mann Whitney U and Wilcoxon Matched Pairs tests were used for statistical analysis, with p<0.05 considered as significant. Results: M4205 (25mg/kg) caused tumor volume shrinkage in UZLX-GIST2B, -GIST25 and GIST882 with relative decrease to 45.6%, 35.1% and 57.3% on the last day as compared to baseline. In UZLX-GIST9 tumor growth to 132.4% was observed in M4205 (25mg/kg)-treated tumors as compared to baseline. In all models we observed significant smaller tumor volumes in M4205 (25mg/kg)-treated tumors compared to control, and this antitumor activity was superior to imatinib in UZLX-GIST9, -GIST2B and GIST882, and to sunitinib in -GIST25. Compared to controls, M4205 (25mg/kg) induced a significant decrease in mitosis (H&E) in all models, confirmed on pHH3 and Ki-67 immunostainings in three models. In -GIST25 and GIST882 grade 2-4 HR with myxoid degeneration was observed in all tumors. All treatments were well tolerated. Conclusion: M4205 has significant antitumor activity in patient- and cell line-derived GIST xenograft models. The novel kinase inhibitor induces volumetric responses, decreases mitotic activity, has antiproliferative effects and in models with KIT exon 13 mutation leads to characteristic myxoid degeneration. * Cornillie et al. Mol Cancer Ther 2019; 18(6):1168-1178 ° Agaram et al. Clin Cancer Res 2007; 13:170-81

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
IDRX-42 IDRX-42 5 1
Drug Name Trade Name Synonyms Drug Classes Drug Description
IDRX-42 M-4205|M 4205|M4205|IDRX 42|IDRX42 KIT Inhibitor 57 IDRX-42 is a specific KIT inhibitor, which potentially decreases mitosis and tumor cell growth (Cancer Res 2022;82(12_Suppl):Abstract nr 2666).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
KIT K642E gastrointestinal stromal tumor predicted - sensitive IDRX-42 Preclinical - Pdx Actionable In a preclinical study, IDRX-42 treatment inhibited mitosis and decreased tumor growth in a cell line xenograft model and a patient-derived xenograft (PDX) model of gastrointestinal stromal tumor harboring KIT K642E (Cancer Res 2022;82(12_Suppl):Abstract nr 2666). detail...
KIT A502_Y503dup gastrointestinal stromal tumor predicted - sensitive IDRX-42 Preclinical - Pdx Actionable In a preclinical study, IDRX-42 treatment inhibited mitosis and decreased tumor growth in a patient-derived xenograft (PDX) model of gastrointestinal stromal tumor harboring KIT A502_Y503dup (Cancer Res 2022;82(12_Suppl):Abstract nr 2666). detail...
KIT W557Lfs*5 KIT P577del KIT D820G gastrointestinal stromal tumor predicted - sensitive IDRX-42 Preclinical - Pdx Actionable In a preclinical study, IDRX-42 treatment inhibited mitosis and decreased tumor growth in a patient-derived xenograft (PDX) model of gastrointestinal stromal tumor harboring KIT P577del, W557Lfs*5, and D820G (Cancer Res 2022;82(12_Suppl):Abstract nr 2666). detail...